{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T16:16:19Z","timestamp":1780589779273,"version":"3.54.1"},"reference-count":26,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2012,9,17]],"date-time":"2012-09-17T00:00:00Z","timestamp":1347840000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:p>The lack of a clear guidance on the adequate number of animals used for positive controls in the short-term (26-weeks) transgenic mouse carcinogenicity studies has resulted in the use of high number of animals. In our earlier Tg.rasH2 studies, 25 mice\/sex were used in the urethane-positive control dose groups that were sacrificed by 18 weeks. Based on a robust response, several of our protocols for Tg.rasH2 studies with 15 mice\/sex and terminal sacrifice at 17 \u00b1 1 weeks were submitted and accepted by the Carcinogenicity Assessment Committee of the US Food and Drug Administration since we demonstrated close to 100% response for the development of lung and splenic tumors (target organs) in 500 mice\/sex. These 500 mice\/sex included 17 groups of 25 mice\/sex and 5 groups of 15 mice\/sex.\u00a0 The objective of this investigation was to determine whether the number of animals can be further reduced along with the shortened duration of exposure to urethane. Accordingly, 10 Tg.rasH2 mice\/sex\/group were administered a total of 3 intraperitoneal (IP) injections of urethane (1000 mg\/kg per day) on study days 1, 3, and 5, and the presence of tumors in the lungs and spleen was evaluated after 8, 10, 12, 14, or 16 weeks. Our results demonstrate that 100% of the mice at 8 weeks had developed lung tumors, whereas close to 100% of the mice at 14 weeks had developed splenic tumors. Based on the development of lung tumors alone in 100% of the mice, we recommend that 10 mice\/sex are sufficient and that these mice can also be sacrificed as early as 10 \u00b1 1 weeks following the administration of urethane.<\/jats:p>","DOI":"10.1177\/1091581812458957","type":"journal-article","created":{"date-parts":[[2012,9,18]],"date-time":"2012-09-18T02:51:57Z","timestamp":1347936717000},"page":"423-429","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Reduction in the Number of Animals and the Evaluation Period for the Positive Control Group in Tg.rasH2 Short-Term Carcinogenicity Studies"],"prefix":"10.1177","volume":"31","author":[{"given":"Sudhir A.","family":"Shah","sequence":"first","affiliation":[{"name":"Division of Toxicology, BioReliance Corporation, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhav. G.","family":"Paranjpe","sequence":"additional","affiliation":[{"name":"Division of Toxicology, BioReliance Corporation, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip I.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Division of Toxicology, BioReliance Corporation, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eias A.","family":"Zahalka","sequence":"additional","affiliation":[{"name":"Division of Toxicology, BioReliance Corporation, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2012,9,17]]},"reference":[{"key":"bibr1-1091581812458957","unstructured":"ICH M3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, 2009 Guideline."},{"key":"bibr2-1091581812458957","unstructured":"International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1997 Guideline S1B Testing for Carcinogenicity in Pharmaceuticals. http:\/\/www.ifpma.org\/ich5s.html."},{"key":"bibr3-1091581812458957","unstructured":"International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use\u2013European Union, Adopted by CPMP, issued as CPMP\/ICH\/299\/95, September 1997."},{"key":"bibr4-1091581812458957","unstructured":"International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use\u2013US, United States Food and Drug Administration, Federal Register, vol 63, page 8983, February 23, 1998."},{"key":"bibr5-1091581812458957","unstructured":"International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use\u2013Japan, Japanese Ministry of Health Welfare, PMSB\/ELD Notification No. 548, July 1998."},{"key":"bibr6-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1177\/019262330002800320"},{"key":"bibr7-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr075"},{"key":"bibr8-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.95103942"},{"key":"bibr9-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1177\/019262339802600401"},{"key":"bibr10-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.5778"},{"key":"bibr11-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1080\/019262301753178609"},{"key":"bibr12-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1080\/01926230490424761"},{"issue":"8","key":"bibr13-1091581812458957","first-page":"1195","volume":"5","author":"Saitoh A","year":"1990","journal-title":"Oncogene"},{"key":"bibr14-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.98106s157"},{"key":"bibr15-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1080\/019262301753178500"},{"key":"bibr16-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1080\/01926230252824851"},{"key":"bibr17-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1080\/019262301753178492"},{"key":"bibr18-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/17.11.2455"},{"key":"bibr19-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(00)00372-4"},{"key":"bibr20-1091581812458957","unstructured":"Shah SA, Paranjpe MG, Zahalka EA. The duration of the evaluation period of the positive control group for RasH2 short-term carcinogenicity studies. Annual Meeting of the Society of Toxicology, Washington, DC. 2011;120(2):569, Abstract #2654."},{"key":"bibr21-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2009.09.002"},{"key":"bibr22-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2005.02.024"},{"key":"bibr23-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(99)00237-2"},{"key":"bibr24-1091581812458957","volume-title":"Annual Meeting of American College of Toxicology","author":"Shah SA","year":"2010"},{"key":"bibr25-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/11.3.463"},{"key":"bibr26-1091581812458957","doi-asserted-by":"publisher","DOI":"10.1021\/tx00022a003"}],"container-title":["International Journal of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1091581812458957","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/1091581812458957","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1091581812458957","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:24:05Z","timestamp":1777458245000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/1091581812458957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,17]]},"references-count":26,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2012,10]]}},"alternative-id":["10.1177\/1091581812458957"],"URL":"https:\/\/doi.org\/10.1177\/1091581812458957","relation":{},"ISSN":["1091-5818","1092-874X"],"issn-type":[{"value":"1091-5818","type":"print"},{"value":"1092-874X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,9,17]]}}}